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ABSTRACT: The peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone transcription factors (PPARα, PPARβ/δ, and PPARγ) is regulated by a wide array of ligands including natural and synthetic chemicals. PPARs have important roles in control of energy metabolism and are known to influence inflammation, differentiation, carcinogenesis, and chemical toxicity. As such, PPARs have been targeted as therapy for common disorders such as cancer, metabolic syndrome, obesity, and diabetes. The recent application of metabolomics, or the global, unbiased measurement of small molecules found in biofluids, or extracts from cells, tissues, or organisms, has advanced our understanding of the varied and important roles that the PPARs have in normal physiology as well as in pathophysiological processes. Continued development and refinement of analytical platforms, and the application of new bioinformatics strategies, have accelerated the widespread use of metabolomics and have allowed further integration of small molecules into systems biology. Recent studies using metabolomics to understand PPARα function, as well as to identify PPARα biomarkers associated with drug efficacy/toxicity and drug-induced liver injury, will be discussed.
Toxicologic Pathology 11/2012; · 1.91 Impact Factor
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ABSTRACT: BACKGROUND: The present study coupled expression profiling with chromatin immunoprecipitation sequencing (ChIP-seq) to examine peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta)-dependent regulation of gene expression in mouse keratinocytes, a cell type that expresses PPARbeta/delta in high concentration. RESULTS: Microarray analysis elucidated eight different types of regulation that modulated PPARbeta/delta-dependent gene expression of 612 genes ranging from repression or activation without an exogenous ligand, repression or activation with an exogenous ligand, or a combination of these effects. Bioinformatic analysis of ChIP-seq data demonstrated promoter occupancy of PPARbeta/delta for some of these genes, and also identified the presence of other transcription factor binding sites in close proximity to PPARbeta/delta bound to chromatin. For some types of regulation, ATF4 is required for ligand-dependent induction of PPARbeta/delta target genes. CONCLUSIONS: PPARbeta/delta regulates constitutive expression of genes in keratinocytes, thus suggesting the presence of one or more endogenous ligands. The diversity in the types of gene regulation carried out by PPARbeta/delta is consistent with dynamic binding and interactions with chromatin and indicates the presence of complex regulatory networks in cells expressing high levels of this nuclear receptor such as keratinocytes. Results from these studies are the first to demonstrate that differences in DNA binding of other transcription factors can directly influence the transcriptional activity of PPARbeta/delta.
BMC Genomics 11/2012; 13(1):665. · 4.07 Impact Factor
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ABSTRACT: The present study examined the effect of prenatal perfluorooctanoic acid (PFOA) administration on pre- and postnatal development using peroxisome proliferator-activated receptor α (PPARα)-humanized mice to determine if species differences in receptor activity that might influence the developmental effects induced by PFOA. Pregnant mice were treated daily with water or PFOA (3 mg/kg) by oral gavage from gestation day 1 (GD1) until GD17 and then either euthanized on GD18, or allowed to give birth and then euthanized on postnatal day (PND) 20. No changes in average fetal weight, crown to rump length or placental weight were observed on GD18. Expression of mRNA encoding the PPARα target genes acyl CoA oxidase (Acox1) and cytochrome P450 4a10 (Cyp4a10) in maternal and fetal liver was increased on GD18 in wild-type and PPARα-humanized mice but not Pparα-null mice. On PND20, relative liver weight was higher in wild-type mice but not in Pparα-null mice or PPARα-humanized mice. Hepatic expression of Acox1 and Cyp4a10 mRNA was higher in wild-type mice but not in Pparα-null mice or PPARα-humanized mice on PND20. The percentage of mice surviving postnatally was lower in wild-type litters but not in litters from Pparα-null mice or PPARα-humanized mice. No changes in pup weight gain, onset of eye opening, or mammary gland development were found in any genotype. Results from these studies demonstrate that the developmental/postnatal effects resulting from prenatal PFOA exposure in mice is differentially mediated by mouse and human PPARα.
Toxicological Sciences 11/2012; · 4.65 Impact Factor
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ABSTRACT: The role of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in Harvey sarcoma ras (Hras)-expressing cells was examined. Ligand activation of PPARβ/δ caused a negative selection with respect to cells expressing higher levels of the Hras oncogene by inducing a mitotic block. Mitosis-related genes that are predominantly regulated by E2F were induced to a higher level in HRAS-expressing Pparβ/δ-null keratinocytes compared to HRAS-expressing wild-type keratinocytes. Ligand-activated PPARβ/δ repressed expression of these genes by direct binding with p130/p107, facilitating nuclear translocation and increasing promoter recruitment of p130/p107. These results demonstrate a novel mechanism of PPARβ/δ cross talk with E2F signaling. Since cotreatment with a PPARβ/δ ligand and various mitosis inhibitors increases the efficacy of increasing G₂/M arrest, targeting PPARβ/δ in conjunction with mitosis inhibitors could become a suitable option for development of new multitarget strategies for inhibiting RAS-dependent tumorigenesis.
Molecular and cellular biology 04/2012; 32(11):2065-82. · 6.06 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is a promising drug target since its agonists increase serum high-density lipoprotein; decrease low-density lipoprotein, triglycerides, and insulin associated with metabolic syndrome; improve insulin sensitivity; and decrease high fat diet-induced obesity. PPARβ/δ agonists also promote terminal differentiation and elicit anti-inflammatory activities in many cell types. However, it remains to be determined whether PPARβ/δ agonists can be developed as therapeutics because there are reports showing either pro- or anti-carcinogenic effects of PPARβ/δ in cancer models. This review examines studies reporting the role of PPARβ/δ in colon, breast, and lung cancers. The prevailing evidence would suggest that targeting PPARβ/δ is not only safe but could have anti-carcinogenic protective effects.
CANCER AND METASTASIS REVIEW 12/2011; 30(3-4):619-40. · 9.35 Impact Factor
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ABSTRACT: Metabolomic analysis will provide the next large set of clues to further our understanding of human health and disease. A recent study has elucidated the significant differences in the metabolomes of adipocytes, serum and an adipocyte cell line after activation of two nuclear receptors, peroxisome proliferator activated receptor β/δ (PPARβ/δ) and PPARγ. These findings hold great promise for explaining fundamental differences in the mechanisms of PPAR agonists and for identifying targets for the treatment of diabetes.See related research article: http://genomebiology.com/2011/12/8/R75.
Genome Medicine 08/2011; 3(8):54.
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ABSTRACT: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) function and receptor cross-talk with other nuclear receptors, including PPARγ and retinoic acid receptors (RARs), was examined using stable human HaCaT keratinocyte cell lines over-expressing PPARβ/δ or PPARγ. Enhanced ligand-induced expression of two known PPAR target genes, adipocyte differentiation-related protein (ADRP) and angiopoietin-like protein 4 (ANGPTL4), was found in HaCaT keratinocytes over-expressing PPARβ/δ or PPARγ. Over-expression of PPARβ/δ did not modulate the effect of a PPARγ agonist on up-regulation of ADRP or ANGPTL4 mRNA in HaCaT keratinocytes. All-trans retinoic acid (atRA) increased expression of a known RAR target gene, yet despite a high ratio of fatty acid binding protein 5 (FABP5) to cellular retinoic acid binding protein II, did not increase expression of ANGPTL4 or 3-phosphoinositide-dependent-protein kinase 1 (PDPK1), even in HaCaT keratinocytes expressing markedly higher levels of PPARβ/δ. While PPARβ/δ-dependent attenuation of staurosporine- or UVB-induced poly (ADP-ribose) polymerase (PARP) cleavage was not observed, PPARβ/δ- and PPARγ-dependent repression of UVB-induced expression and secretion of inflammatory cytokines was found in HaCaT keratinocytes over-expressing PPARβ/δ or PPARγ. These studies suggest that FABP5 does not transport atRA or GW0742 to PPARβ/δ and promote anti-apoptotic activity by increasing expression of PDPK1, or that PPARβ/δ interferes with PPARγ transcriptional activity. However, these studies demonstrate that stable over-expression of PPARβ/δ or PPARγ significantly increases the efficacy of ligand activation and represses UVB-induced expression of tumor necrosis factor α (TNFα), interleukin 6 (IL6), or IL8 in HaCaT keratinocytes, thereby establishing an excellent model to study the functional role of these receptors in human keratinocytes.
Cellular signalling 08/2011; 23(12):2039-50. · 4.09 Impact Factor
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ABSTRACT: This study critically examined the role of PPARβ/δ in colon cancer models. Expression of PPARβ/δ mRNA and protein was lower and expression of CYCLIN D1 protein higher in human colon adenocarcinomas compared to matched non-transformed tissue. Similar results were observed in colon tumors from Apc(+/Min-FCCC) mice compared to control tissue. Dietary administration of sulindac to Apc(+/Min-FCCC) mice had no influence on expression of PPARβ/δ in normal colon tissue or colon tumors. Cleaved poly (ADP-ribose) polymerase (PARP) was either increased or unchanged, while expression of 14-3-3ε was not influenced in human colon cancer cell lines cultured with the PPARβ/δ ligand GW0742 under conditions known to increase apoptosis. While DLD1 cells exhibited fewer early apoptotic cells after ligand activation of PPARβ/δ following treatment with hydrogen peroxide, this change was associated with an increase in late apoptotic/necrotic cells, but not an increase in viable cells. Stable over-expression of PPARβ/δ in human colon cancer cell lines enhanced ligand activation of PPARβ/δ and inhibition of clonogenicity in HT29 cells. These studies are the most quantitative to date to demonstrate that expression of PPARβ/δ is lower in human and Apc(+/Min-FCCC) mouse colon tumors than in corresponding normal tissue, consistent with the finding that increasing expression and activation of PPARβ/δ in human colon cancer cell lines inhibits clonogenicity. Because ligand-induced attenuation of early apoptosis can be associated with more late, apoptotic/necrotic cells, but not more viable cells, these studies illustrate why more comprehensive analysis of PPARβ/δ-dependent modulation of apoptosis is required in the future.
Molecular Carcinogenesis 03/2011; 50(11):884-900. · 3.16 Impact Factor
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ABSTRACT: Ligand activation of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) and inhibition of cyclooxygenase-2 (COX2) activity by nonsteroidal anti-inflammatory drugs (NSAID) can both attenuate skin tumorigenesis. The present study examined the hypothesis that combining ligand activation of PPARβ/δ with inhibition of COX2 activity will increase the efficacy of chemoprevention of chemically induced skin tumorigenesis over that observed with either approach alone. To test this hypothesis, wild-type and Pparβ/δ-null mice were initiated with 7,12-dimethylbenz[a]anthracene (DMBA), topically treated with 12-O-tetradecanoylphorbol-13-acetate to promote tumorigenesis, and then immediately treated with topical application of the PPARβ/δ ligand GW0742, dietary administration of the COX2 inhibitor nimesulide, or both GW0742 and nimesulide. Ligand activation of PPARβ/δ with GW0742 caused a PPARβ/δ-dependent delay in the onset of tumor formation. Nimesulide also delayed the onset of tumor formation and caused inhibition of tumor multiplicity (46%) in wild-type mice but not in Pparβ/δ-null mice. Combining ligand activation of PPARβ/δ with dietary nimesulide resulted in a further decrease of tumor multiplicity (58%) in wild-type mice but not in Pparβ/δ-null mice. Biochemical and molecular analysis of skin and tumor samples show that these effects were due to the modulation of terminal differentiation, attenuation of inflammatory signaling, and induction of apoptosis through both PPARβ/δ-dependent and PPARβ/δ-independent mechanisms. Increased levels and activity of PPARβ/δ by nimesulide were also observed. These studies support the hypothesis that combining ligand activation of PPARβ/δ with inhibition of COX2 activity increases the efficacy of preventing chemically induced skin tumorigenesis as compared with either approach alone.
Molecular Cancer Therapeutics 12/2010; 9(12):3267-77. · 5.23 Impact Factor
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ABSTRACT: To commemorate the 50th anniversary of the Society of Toxicology, this special edition article reviews the history and current scope of xenobiotic metabolism and transport, with special emphasis on the discoveries and impact of selected "xenobiotic receptors." This overall research realm has witnessed dynamic development in the past 50 years, and several of the key milestone events that mark the impressive progress in these areas of toxicological sciences are highlighted. From the initial observations regarding aspects of drug metabolism dating from the mid- to late 1800's, the area of biotransformation research witnessed seminal discoveries in the mid-1900's and onward that are remarkable in retrospect, including the discovery and characterization of the phase I monooxygenases, the cytochrome P450s. Further research uncovered many aspects of the biochemistry of xenobiotic metabolism, expanding to phase II conjugation and phase III xenobiotic transport. This led to hallmark developments involving integration of genomic technologies to elucidate the basis for interindividual differences in response to xenobiotic exposures and discovery of nuclear and soluble receptor families that selectively "sense" the chemical milieu of the mammalian cell and orchestrate compensatory changes in gene expression programming to accommodate complex xenobiotic exposures. This review will briefly summarize these developments and investigate the expanding roles of xenobiotic receptor biology in the underlying basis of toxicological response to chemical agents.
Toxicological Sciences 11/2010; 120 Suppl 1:S49-75. · 4.65 Impact Factor
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ABSTRACT: Recent work indicates that PPARalpha is required for perfluorooctanoic acid (PFOA)-induced postnatal lethality resulting from prenatal exposure. The present study tested the hypothesis that relatively modest activation of PPARalpha during prenatal development will cause postnatal lethality, similar to that observed with PFOA, a relatively low affinity PPARalpha agonist. Female wild-type and Pparalpha-null mice were mated overnight with males of the same genotype. The presence of a copulatory plug on the morning after mating was indicative of pregnancy and considered gestation day (GD) 0. Plugged female mice were fed either a control diet or one containing clofibrate (0.5%) or Wy-14,643 (0.005%) until GD18 or until parturition. Mice were examined on GD18 or on postnatal day (PND) 20 following the prenatal exposure period. Dietary administration of clofibrate or Wy-14,643 did not affect maternal weight or weight gain, the average number of implantations, the percentage of litter loss, the average number of live/dead fetuses, average crown-rump length, or the average fetal weight on GD18 in either genotype. An increase in relative maternal liver weight and elevated expression of PPARalpha target genes in maternal and fetal livers on GD18 were observed, indicative of PPARalpha-dependent changes in both the maternal and fetal compartments. However, no defects in postnatal development were observed by either clofibrate or Wy-14,643 in either genotype by PND20. These results demonstrate that relatively low level activation of PPARalpha by clofibrate or Wy-14,643 during prenatal development does not cause postnatal lethality.
Toxicology 09/2010; 276(1):79-84. · 3.68 Impact Factor
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Prajakta S Palkar,
Michael G Borland,
Simone Naruhn,
Christina H Ferry,
Christina Lee,
Ugir H Sk,
Arun K Sharma,
Shantu Amin,
Iain A Murray,
Cherie R Anderson,
Gary H Perdew,
Frank J Gonzalez,
Rolf Müller, Jeffrey M Peters
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ABSTRACT: The availability of high-affinity agonists for peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) has led to significant advances in our understanding of the functional role of PPARbeta/delta. In this study, a new PPARbeta/delta antagonist, 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), was characterized using in vivo and in vitro models. Orally administered GSK3787 caused antagonism of 4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid (GW0742)-induced up-regulation of Angptl4 and Adrp mRNA expression in wild-type mouse colon but not in Pparbeta/delta-null mouse colon. Chromatin immunoprecipitation (ChIP) analysis indicates that this correlated with reduced promoter occupancy of PPARbeta/delta on the Angptl4 and Adrp genes. Reporter assays demonstrated antagonism of PPARbeta/delta activity and weak antagonism and agonism of PPARgamma activity but no effect on PPARalpha activity. Time-resolved fluorescence resonance energy transfer assays confirmed the ability of GSK3787 to modulate the association of both PPARbeta/delta and PPARgamma coregulator peptides in response to ligand activation, consistent with reporter assays. In vivo and in vitro analysis indicates that the efficacy of GSK3787 to modulate PPARgamma activity is markedly lower than the efficacy of GSK3787 to act as a PPARbeta/delta antagonist. GSK3787 antagonized GW0742-induced expression of Angptl4 in mouse fibroblasts, mouse keratinocytes, and human cancer cell lines. Cell proliferation was unchanged in response to either GW0742 or GSK3787 in human cancer cell lines. Results from these studies demonstrate that GSK3787 can antagonize PPARbeta/delta in vivo, thus providing a new strategy to delineate the functional role of a receptor with great potential as a therapeutic target for the treatment and prevention of disease.
Molecular pharmacology 09/2010; 78(3):419-30. · 4.53 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. Herein, we describe an efficient synthesis of a novel isosteric selenium analog of the highly specific PPARbeta/delta ligand 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516; 1). The study examined the efficiency of the novel selenium analog 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-selenazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (2) to activate PPARbeta/delta and the effect of ligand activation of PPARbeta/delta on cell proliferation and target gene expression in human HaCaT keratinocytes. The results showed that similar to GW501516, the Se-analog 2 increased expression of the known PPARbeta/delta target gene angiopoietin-like protein 4 (ANGPTL4); the compound 2 was comparable in efficacy as compared to GW501516. Consistent with a large body of evidence, the Se-analog inhibited cell proliferation in HaCaT keratinocytes similar to that observed with GW501516. In summary, the novel Se-analog 2 has been developed as a potent PPARbeta/delta ligand that may possess additional anti-cancer properties of selenium.
Bioorganic & medicinal chemistry letters 07/2010; 20(14):4050-2. · 2.65 Impact Factor
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ABSTRACT: Previous studies showed that natural prenyloxyphenylpropanoid derivatives have potent biological properties in vivo. Given the structural similarities between these compounds and known peroxisome proliferator-activated receptor (PPAR) agonists, the present study examined the hypothesis that propenoic acid derivatives activate PPARs.
Chimeric reporter assays were performed to identify propenoic acid derivates that could activate PPARs. Quantitative polymerase chain reaction (qPCR) analysis of wild-type and Pparbeta/delta-null mouse primary keratinocytes was performed to determine if a test compound could specifically activate PPARbeta/delta. A human epithelial carcinoma cell line and primary mouse keratinocytes were used to determine the effect of the compound on cell proliferation.
Three of the propenoic acid derivatives activated PPARs, with the greatest efficacy being observed with prenyloxycinnamic acid derivatives 4'-geranyloxyferulic acid (compound 1) for PPARbeta/delta. Compound 1 increased expression of a known PPARbeta/delta target gene through a mechanism that requires PPARbeta/delta. Inhibition of cell proliferation by compound 1 was found in a human epithelial carcinoma cell line.
Results from these studies demonstrate that compound 1 can activate PPARbeta/delta and inhibit cell proliferation of a human skin cancer cell line, suggesting that the biological effects of 4'-geranyloxyferulic acid may be mediated in part by activating this PPAR isoform.
Life sciences 02/2010; 86(13-14):493-8. · 2.56 Impact Factor
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ABSTRACT: Ligand activation of peroxisome proliferator-activated receptor (PPAR)-beta/delta and inhibition of cyclooxygenase-2 (COX-2) activity by nonsteroidal anti-inflammatory drugs can attenuate skin tumorigenesis. There is also evidence that attenuation of skin tumorigenesis by inhibition of COX-2 activity occurs through PPARbeta/delta-independent mechanisms. The present study examined the hypothesis that combining ligand activation of PPARbeta/delta with inhibition of COX-2 activity will cooperatively inhibit chemically induced skin tumor progression using both in vivo and ex vivo models. A two-stage chemical carcinogenesis bioassay was performed in wild-type and Pparbeta/delta-null mice. After 22 weeks, cohorts of both mouse lines were divided into four experimental groups: (1) control, (2) topical application of the PPARbeta/delta ligand GW0742, (3) dietary administration of the COX-2 inhibitor nimesulide, or (4) both GW0742 and nimesulide. Ligand activation of PPARbeta/delta did not influence skin tumor progression, while a modest decrease in skin tumor multiplicity was observed with dietary nimesulide. Interestingly, the combined treatment of GW0742 and nimesulide increased the efficacy of the decrease in papilloma multiplicity for 6 weeks in wild-type mice, but this effect was not found at later time points and was not found in similarly treated Pparbeta/delta-null mice. Neoplastic keratinocyte lines cultured with GW0742 and nimesulide also exhibited enhanced inhibition of cell proliferation coincident with increased expression of Keratin messenger RNAs. Results from these studies support the hypothesis that combining ligand activation of PPARbeta/delta with inhibition of COX-2 activity can inhibit chemically induced skin tumor progression by modulating differentiation.
Toxicological Sciences 09/2009; 113(1):27-36. · 4.65 Impact Factor
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ABSTRACT: The effects of ligand activation of PPARbeta/delta were examined in the mouse mammary tumor cell line (C20). Expression of PPARbeta/delta was markedly lower in C20 cells as compared to the human non-tumorigenic mammary gland derived cell line (MCF10A) and mouse keratinocytes. Ligand activation of PPARbeta/delta in C20 cells caused upregulation of the PPARbeta/delta target gene angiopoietin-like 4 (Angptl4). Inhibition of C20 cell proliferation and clonogenicity was observed following treatment with GW0742 or GW501516, two highly specific PPARbeta/delta ligands. In addition, an increase in apoptosis was observed in C20 cells cultured with 10microM GW501516 that preceded the observed inhibition of cell proliferation. Results from this study show that proliferation of the C20 mouse mammary gland cancer cell line is inhibited by ligand activation of PPARbeta/delta due in part to increased apoptosis.
Cancer letters 09/2009; 288(2):219-25. · 4.86 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) has many beneficial physiological functions ranging from enhancing fatty acid catabolism, improving insulin sensitivity, inhibiting inflammation and increasing oxidative myofibers allowing for improved athletic performance. Thus, given the potential for targeting PPARbeta/delta for the prevention and/or treatment of diseases including diabetes, dyslipidemias, metabolic syndrome and cancer, it is critical to clarify the functional role of PPARbeta/delta in cell proliferation and associated disorders such as cancer. However, there is considerable controversy whether PPARbeta/delta stimulates or inhibits cell proliferation. This review summarizes the literature describing the influence of PPARbeta/delta on cell proliferation, with an emphasis toward dissecting the data that give rise to opposing hypotheses. Suggestions are offered to standardize measurements associated with these studies so that interlaboratory comparisons can be accurately assessed.
Biochimica et Biophysica Acta 07/2009; 1796(2):230-41. · 4.66 Impact Factor
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ABSTRACT: Studies indicate that peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) can either attenuate or potentiate colon cancer. One hypothesis suggests that PPAR beta/delta is upregulated by the adenomatous polyposis coli (APC)/beta-CATENIN pathway and a related hypothesis suggests that PPAR beta/delta is downregulated by nonsteroidal antiinflammatory drugs (NSAIDs). The present study examined these possibilities using in vivo and in vitro models. While APC/beta-CATENIN-dependent expression of CYCLIN D1 was observed in vivo and in vitro, expression of PPAR beta/delta was not different in colon or intestinal polyps from wild-type or Apc(min) heterozygous mice or in human colon cancer cell lines with mutations in APC and/or beta-CATENIN. No difference in the level of PPAR beta/delta was found in colon from wild-type or Apc(min) heterozygous mice following treatment with NO-donating aspirin (NO-ASA). NSAIDs inhibited cell growth in RKO (wild-type APC) and DLD1 (mutant APC) human colon cancer cell lines but expression of PPAR beta/delta was not downregulated in these cell lines in response to a broad concentration range of celecoxib, indomethacin, NS-398, or nimesulide. However, indomethacin caused an increase in PPAR beta/delta mRNA and protein that was accompanied with increased expression of a known PPAR beta/delta target gene. Interestingly, expression of PPAR alpha was also increased in the human colon cancer cell lines by several NSAIDs at the highest concentration examined. Results from these studies provide additional evidence indicating that PPAR beta/delta is not upregulated by the APC/beta-CATENIN pathway. Further, these studies suggest that increased PPAR beta/delta and/or PPAR alpha by NSAIDs in human colon cancer cell lines could contribute to the mechanisms underlying the chemopreventive effects of NSAIDs.
Molecular Carcinogenesis 06/2009; 48(10):942-52. · 3.16 Impact Factor
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ABSTRACT: Studies indicate that peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) can either attenuate or potentiate colon cancer. One hypothesis suggests that PPARβ/δ is upregulated by the adenomatous polyposis coli (APC)/β-CATENIN pathway and a related hypothesis suggests that PPARβ/δ is downregulated by nonsteroidal antiinflammatory drugs (NSAIDs). The present study examined these possibilities using in vivo and in vitro models. While APC/β-CATENIN-dependent expression of CYCLIN D1 was observed in vivo and in vitro, expression of PPARβ/δ was not different in colon or intestinal polyps from wild-type or Apcmin heterozygous mice or in human colon cancer cell lines with mutations in APC and/or β-CATENIN. No difference in the level of PPARβ/δ was found in colon from wild-type or Apcmin heterozygous mice following treatment with NO-donating aspirin (NO-ASA). NSAIDs inhibited cell growth in RKO (wild-type APC) and DLD1 (mutant APC) human colon cancer cell lines but expression of PPARβ/δ was not downregulated in these cell lines in response to a broad concentration range of celecoxib, indomethacin, NS-398, or nimesulide. However, indomethacin caused an increase in PPARβ/δ mRNA and protein that was accompanied with increased expression of a known PPARβ/δ target gene. Interestingly, expression of PPAR was also increased in the human colon cancer cell lines by several NSAIDs at the highest concentration examined. Results from these studies provide additional evidence indicating that PPARβ/δ is not upregulated by the APC/β-CATENIN pathway. Further, these studies suggest that increased PPARβ/δ and/or PPAR by NSAIDs in human colon cancer cell lines could contribute to the mechanisms underlying the chemopreventive effects of NSAIDs. Mol. Carcinog. © 2009 Wiley-Liss, Inc.
Molecular Carcinogenesis 05/2009; 48(10):942 - 952. · 3.16 Impact Factor
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ABSTRACT: Perfluorobutyrate (PFBA) is a short chain perfluoroalkyl carboxylate that is structurally similar to perfluorooctanoate. Administration of PFBA can cause peroxisome proliferation, induction of peroxisomal fatty acid oxidation and hepatomegaly, suggesting that PFBA activates the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha). In this study, the role of PPAR-alpha in mediating the effects of PFBA was examined using PPAR-alpha null mice and a mouse line expressing the human PPAR-alpha in the absence of mouse PPAR-alpha (PPAR-alpha humanized mice). PFBA caused upregulation of known PPAR-alpha target genes that modulate lipid metabolism in wild-type and PPAR-alpha humanized mice, and this effect was not found in PPAR-alpha null mice. Increased liver weight and hepatocyte hypertrophy were also found in wild-type and humanized PPAR-alpha mice treated with PFBA, but not in PPAR-alpha null mice. Interestingly, hepatocyte focal necrosis with inflammatory cell infiltrate was only found in wild-type mice administered PFBA; this effect was markedly diminished in both PPAR-alpha null and PPAR-alpha humanized mice. Results from these studies demonstrate that PFBA can modulate gene expression and cause mild hepatomegaly and hepatocyte hypertrophy through a mechanism that requires PPAR-alpha and that these effects do not exhibit a species difference. In contrast, the PPAR-alpha-dependent increase in PFBA-induced hepatocyte focal necrosis with inflammatory cell infiltrate was mediated by the mouse PPAR-alpha but not the human PPAR-alpha. Collectively, these findings demonstrate that PFBA can activate both the mouse and human PPAR-alpha, but there is a species difference in the hepatotoxic response to this chemical.
Toxicological Sciences 05/2009; 110(1):204-11. · 4.65 Impact Factor
